Multiple myeloma (MM) is an incurable and fatal clonal plasma cell (PC) malignancy. All MM cases are preceded by a highly prevalent asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) or a less prevalent, more advanced stage called smoldering MM (SMM). MGUS and SMM patients exhibit significant risk of progression to MM, with rates estimated at 1% and 10% per year, respectively. Importantly, a diagnosis of MM depends on overt clinical manifestations of serious end-organ damage. Therefore, treatment is not initiated before evolving MGUS and SMM patients reach an advanced disease stage. Because currently identified risk factors lack sufficient accuracy to justify treatment initiation of asymptomatic patients using agents with considerable toxicities, our specific goal is to identify accurate biomarkers that detect the earliest stage of PC malignant transformation such that MGUS and SMM patients in the process of progressing can be identified prior to the onset of serious end-organ damage. A number of useful prognostic factors have been identified, however, the field still lacks an accurate and sensitive biomarker(s) that identifies MGUS and SMM patients who, in spite of being asymptomatic, have begun to progress. Although MGUS and SMM PCs harbor genetic lesions typical of MM, they can somewhat surprisingly remain remarkably stable for years suggesting the presence of a currently unknown barrier(s) to further expansion. Because these initial lesions are insufficient to cause symptomatic disease, the critical question that needs to be answered is what are the specific biological/genetic changes that occur to permit the abnormal PC clone to overcome this barrier(s) in patients who progress to MM? In this regard, it is notable that common themes observed during malignant progression include metabolic changes, remodeling of the tumor microenvironment (ME), and increased cell proliferation, all of which have also been identified in MM. In preliminary studies, we have obtained provocative evidence that the transmembrane CD147 molecule, also known as EMMPRIN (extracellular matrix metalloproteinase [MMP] inducer), may be playing an important biological role in MM PCs and that its expression may become induced during disease progression. Thus, we hypothesize that CD147 is not only an exceptionally promising biomarker of MGUS and SMM progression, but that malignant PCs require its expression for growth and survival as well as for its ability to modify the ME in a manner that fosters further disease progression. Two aims are proposed. Aim 1 will evaluate the ability of PC CD147 expression to identify asymptomatic MGUS and SMM patients with evolving disease. Aim 2 will elucidate the role of CD147 in MM cell proliferation and modification of the tumor ME. The overall impact of our study derives from the mechanistic insights that will be gained and the discovery of an important role for CD147 in progression to MM. Furthermore, demonstration that this molecule is required for disease progression and/or pathogenesis would also foster development of novel targeted therapies to CD147. PUBLIC HEALTH RELEVANCE: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to the typically fatal plasma cell (PC) cancer, multiple myeloma (MM). Currently, we lack accurate biomarkers able to detect patients in the process of progressing prior to serious end-organ damage. Our data suggest that the CD147 molecule is an exceptionally promising biomarker of MGUS and SMM progression and we hypothesize that it is essential for malignant PC proliferation and modification of the tumor microenvironment. Our overall goal is to identify MGUS and SMM patients with evolving disease and define therapeutic targets that might uniquely eliminate the evolving abnormal PCs.